CT041 - Monotherapy dose escalation of davoceticept (ALPN-202), a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1)
Publication Title
AACR American Association for Cancer Research: Annual Meeting 2022
Document Type
Abstract
Publication Date
4-12-2022
Keywords
oregon; portland; chiles
Abstract
Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recognized as a key target of checkpoint inhibition. Davoceticept (ALPN-202) is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in vitro and in in vivo tumor models, while demonstrating favorable preclinical safety.
Methods: This is a first-in-human, cohort-based, open-label dose escalation and expansion study of davoceticept in adults with advanced solid tumors or lymphoma (NCT04186637). Patients with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity. Disease assessments are evaluated by RECIST v1.1 for solid tumors. A prior presentation discussed the initial first 5 cohorts of the Q1W schedule; this presentation includes the remainder of dose escalation, including the Q3W schedule.
Results: As of December 2021, 57 adults with various advanced solid tumors, most commonly colorectal and pancreatic, received davoceticept monotherapy, which was well tolerated through 10 mg/kg Q3W. Davoceticept demonstrated dose-dependent PK and target saturation. Immune-related adverse events (irAEs), occurred in 20/54 (35%), mostly involving the skin, endocrine and gastrointestinal systems. All but 2 of the irAE were grade 1-2. One DLT, chronic active gastritis grade 3, was observed at 3 mg/kg Q3W. Among 47 evaluable, unconfirmed partial responses were observed in 2 (colorectal carcinoma and renal cell carcinoma). Stable disease, defined as first scan at 6 weeks, was observed in 22; 9 (41%) demonstrated tumor volume reduction, 2 (9%) demonstrated SD for > 6 months, and 1 has an ongoing SD at 8 months. At doses above 0.1 mg/kg, pharmacodynamic ex vivo analyses demonstrated agonistic engagement of CD28 on T cells, and flow cytometry demonstrated increased circulating activated (ICOS+) and proliferating (Ki-67+) T cells, increased central memory T cells, and reduced regulatory T cells, consistent with active CD28 engagement.
Conclusion: First-in-human dose escalation with davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity in a largely treatment-refractory, non-immunogenic tumor population. These findings suggest a potential additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and demonstrate further rationale for combination development. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned.
Area of Special Interest
Cancer
Specialty/Research Institute
Earle A. Chiles Research Institute
Specialty/Research Institute
Oncology
Comments
Michael Millward, Justin C. Moser, Diwakar Davar, Mark Voskoboynik, Nehal J. Lakhani, Rachel E. Sanborn, Jaspreet Grewal, Ajita Narayan, Mario Sznol, Keren Schieber, Hany Zayed, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. Linear Clinical Research & University of Western Australia, Perth, Australia, HonorHealth Research and Innovation Institute, Scottsdale, AZ, University of Pittsburgh Medical Center, Pittsburgh, PA, The Alfred Hospital, Melbourne, Australia, START Midwest, Grand Rapids, MI, Earle A. Chiles Research Institute, Portland, OR, Norton Cancer Institute, Louisville, KY, Horizon Oncology Research, Lafayette, IN, Yale Cancer Center, New Haven, CT, Alpine Immune Sciences, Seattle, WA, PRA Health Sciences, Singapore, Singapore, PRA Health Sciences, San Diego, CA